Preparation of 2-aryl carbapenems via a boronic acid coupling reaction

ABSTRACT

The present invention is directed to a process of making 2-Aryl Carbapenems of Formula 1 from a compound of formula 2. ##STR1##

This is a division of application Ser. No. 07/978,598 filed Nov. 19,1992, now U.S. Pat. No. 5,338,875 issued on Aug. 16, 1994, priority ofwhich is claimed hereunder.

BACKGROUND OF THE INVENTION

The invention disclosed herein concerns a process of making 2-arylcarbapenems. Carbapenem antibiotics, particularly thienamycin andimipenem (see U.S. Pat. Nos. 3,950,377 and 4,194,047) are well known fortreating a broad spectrum of gram-negative and gram-positive bacterialinfections. Active 2-Aryl substituted Carbapenem include those disclosedin U.S. Pat. Nos. 5,034,384 and 5,011,832.

As is generally appreciated by those with skill in the art, theCarbapenem nucleus is unstable, thus necessitating mild couplingreagents. The present methods of coupling utilize toxic reagents. Forexample, one alternative procedure utilizes highly toxic stannanereagents. The stannane procedure also introduces toxic impurities whichmade purification of the product and subsequent processing difficult.

Processes disclosed in the prior art include the following:

Coupling to produce 2-aryl carbapenems was previously performed viastannane chemistry (Rano et al. Tetrahedron Letters 1990, 2853). Relatedcouplings with β-lactam containing substrates are given by Monroe andMcDonald (Journal of Organic Chemistry 1989, 54, 5828), Kant(Tetrahedron Letters 1990, 3389), and Farina (Tetrahedron Letters 1988,5739, 6043). Boronic acid or ester couplings were reported by Snieckus(Tetrahedron Letters 1990, 1665), Suzuki (Chem. Letters 1989, 1405;Journal of the American Chemical Society 1985, 107, 972).

In sharp contrast, the boronic acid coupling methodology disclosedherein present mild conditions, low toxicity and ease of productpurification.

Selected examples of the generalized palladium catalyzed coupling oforganometallic agents with enol triflates are reported by Scott andMcMurry (Accounts of Chemical Research, 1988, 21, 47), Stille (Agnew.Chem International Edition English, 1986, 25, 508) and Piers(Tetrahedron Letters 1991, 4555).

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to a process of making 2-ArylCarbapenems of formula 1 from a compound of Formula 2: ##STR2##

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention concerns a process of making 2-arylcarbapenem intermediates of Formula 1, ##STR3## wherein Ar is ##STR4##wherein R^(a) is

(a) CN,

(b) CF₃,

(c) C₁₋₃ alkoxy,

(d) --NO₂,

(e) hydroxy C₁₋₃ alkyl, wherein the hydroxy is optionally protected witha silyl protecting group selected from tri-C₁₋₄ alkyl silyl, phenyl diC₁₋₄ alkyl and diphenyl mono C₁₋₄ alkyl silyl; or

(f) substituted tetrazolyl wherein the substitutent is hydrogen, C₁₋₃alkyl, halo, hydroxy or C₁₋₃ alkoxy;

R^(b) is

(a) C₁₋₃ alkyl,

(b) C₁₋₃ alkoxy,

(c) substituted C₁₋₃ alkyl, wherein the substituent is hydroxy, or

(d) hydroxy C₁₋₃ alkyl, wherein the hydroxy is optionally protected witha silyl protecting group selected from tri-C₁₋₄ alkyl silyl, phenyl diC₁₋₄ alkyl and diphenyl mono C₁₋₄ alkyl silyl;

R^(c) is

(a) C₁₋₃ alkyl,

(b) hydroxy C₁₋₃ alkyl, wherein the hydroxy is optionally protected witha silyl protecting group selected from tri-C₁₋₄ alkyl silyl, phenyl diC₁₋₄ alkyl and diphenyl mono C₁₋₄ alkyl silyl;

R₁ is a conventional protecting group, such as, but not limited to

(a) benzyl,

(b) p-methoxybenzyl,

(c) p-nitrobenzyl,

(d) o-nitrobenzyl,

(e) benzhydryl

(f) allyl,

(g) 2-trimethylsilylethyl or

(h) 2,2,2-trichloroethyl;

R₃ is

(a) hydrogen,

(b) a hydroxy protecting group selected from tri-C₁₋₄ alkyl silyl,phenyl di C₁₋₄ alkyl and diphenyl mono C₁₋₄ alkyl silyl;

(c) --C(O)OR'₃, wherein R'₃ is

(a) benzyl,

(b) p-methoxybenzyl,

(c) p-nitrobenzyl,

(d) o-nitrobenzyl,

(e) benzhydryl

(f) allyl,

(g) 2-trimethylsilylethyl or

(h) 2,2,2-trichloroethyl;

(d) CH₂ OR'₃, or

(e) R'₃ ;

R₇ is hydrogen or methyl, including β-methyl;

(A) contacting a compound of Formula 2 ##STR5## in a non-reactivesolvent with an activating agent in the presence of a base to yield acompound of formula A; ##STR6## wherein --OR₂ is a good leaving groupsuch as (a) triflate,

(b) fluorosulfonate,

(c) mesylate,

(d) rosylate,

(e) diaryl phosphate wherein the aryl group is mono or disubstitutedphenyl and the substituents are each independently hydrogen or haloincluding chloro;

For purposes of this specification non-reactive solvents includehalocarbon solvents such solvents as mono or di-halo C₁₋₄ alkylincluding dichloromethane; etheral solvents such as diethyl etherdi-n-butyl and diisopropyl ethers, cyclic ethers such astetrahydropyran, and tetrahydrofuran; aromatic solvents such as benzene,toluene and xylene; and C₆₋₁₀ linear, branched or cyclic hydrocarbonsolvent including hexane. Activating agents are defined to includebis-(3-chlorophenyl) chlorophosphate, diphenyl chlorophosphate,fluorosulfonic anhydride and trifluoromethanesulfonic anhydride, orothers that will yield the substituent --OR₂. Suitable bases include butare not limited to pyrrole, pyridine, pyrrolidine, imidazole andlutidine, di C₁₋₃ alkylamine such as diisopropylamine and tri C₁₋₃alkylamine such as triethylamine and diisopropyl ethylamine, metalamides, wherein metal is defined as sodium, potassium or lithium,including di-C₁₋₄ alkyl amides such as lithium diisopropylamide; C₁₋₄alkyl metals such as n-butyllithium; metal C₁₋₄ alkoxides, such aspotassium t-butoxide; metal hydrides such as sodium or potassiumhydride; and metal carbonates sodium and potassium carbonates. The molarratio of activating agent to Formula 2 should be approximately 0.90 to1.0, but preferably not greater. A ratio of 0.95 is typical. Thereaction may be conducted from approximately -20° C. to -80° C.preferably -70° C. to -80° C. The reaction is allowed to proceed untilsubstantially complete in approximately 0.25-2 hours, typically 0.25-1.0hours. The reaction is preferably conducted under nitrogen.

(B) Contacting the compound of formula A in non-reactive solvent asdefined above, with a protecting agent suitable for removably protectingthe hydroxyl of Formula 2 in the presence of a nitrogen containing baseto yield a compound of Formula B; ##STR7## wherein the protecting agentis R₃ X, consisting of a protecting group R₃ and a good leaving group X.

For purposes of this specification, the protecting groups (R₃) suitablefor step (B) include tri-organo silyl groups such as tri-C₁₋₃ alkylsilyl, including tri-methyl and tri-ethyl silyl and t-butyl di-methylsilyl. Also included is t-butyl di-phenylsilyl. Good leaving groups aredefined to include chloro and triflate. Other suitable groups are foundin Protective Groups in Organic Synthesis, Theodora W. Green, John Wileyand Sons 1981.

The nitrogen containing bases are defined as above. The molar ratio ofcompound A to the protecting agent should be approximately 1 to 1 orgreater. The reaction should be allowed to proceed until complete andapproximately 0.25 to 1.5 hours. The reaction may be conducted from -20°C. to -80° C. The reaction is preferably conducted under nitrogen.

As shown in the Example, preferably Step (B) is conducted in situ withthe reaction mixture resulting from Step (A). Alternatively, Compound Acan be isolated by standard means before continuing with the reactionscheme.

(C) Contacting the compound of Formula B and a coupling base in acoupling solvent with a compound of formula ##STR8## and a transitionmetal catalyst to yield a compound of Formula 1, ##STR9## wherein R₄ andR₅ are each individually hydrogen or C₁₋₆ alkyl or R₄ and R₅ takentogether are C₁₋₆ alkyl or R₄ and R₅ are joined together as to form##STR10## wherein R₆ is C₁₋₃ alkyl, halo, hydroxy, C₁₋₃ alkoxy orhydrogen.

For purposes of this specification coupling bases include but are notlimited to metal hydroxides including barium, potassium, sodium, orlithium, thallium hydroxides; metal C₁₋₄ alkoxide such as sodium,potassium or lithium t-butoxide; and metal carbonate such as potassiumor sodium carbonates. The coupling solvent is defined to include di-C₁₋₃alkyl formamide such as dimethyl formamide, di-C₁₋₃ alkyl sulfoxide suchas dimethylsulfoxide, N-methylpyrrolidinone, N-ethylpyrrolidinone.##STR11## as well as halocarbon solvents such solvents as mono ordi-halo C₁₋₄ alkyl including dichloromethane; etheral solvents such asdiethyl ether di-n-butyl and diisopropyl ethers, cyclic ethers such astetrahydropyran, and tetrahydrofuran; aromatic solvents such as benzene,toluene and xylene; and C₆₋₁₀ linear, branched or cyclic hydrocarbonsolvent including hexane.

For purposes of this specification non-reactive solvents includehalocarbon solvents such as mono or di-halo C₁₋₄ alkyl includingdichloromethane.

Optionally, a standard phase transfer agent such astetra-n-butylammonium salts and polyethylglycol reagents such as TWEEN40 may be added to the reaction mix (0 to 5% of total volume).

The molar ratio of compound B to ##STR12## should be approximately 1 to1 or greater; preferably 1.2 to 1. The molar ratio of palladium catalystto compound B should be approximately 0.01 or greater; preferably 0.06to 0.10. The reaction is allowed to proceed until substantially completein 1-24 hours (solvent dependent).

For purposes of this specification transition metal catalyst is definedto include Pd° catalysts including Pd (dba)₂, Pd₂ (dba)₃, Pd₂(dba)₃.CHCl₃ wherein dba is defined as dibenzyledineacetone. Asappreciated by those of skill in the art, other standard coordinatingligands may also be used. Pd^(II) catalysts may also be employedincluding Pd(OAc)₂ and PdCl₂. Nickel catalysts may also be used.

The compound of Formula 1 can then be converted to active antibiotic bymethods known in the art, as exemplified in U.S. Pat. Nos. 5,034,384 and5,011,832 which are hereby incorporated by reference.

In a second embodiment the invention concerns intermediate compounds offormula ##STR13## as defined above. ##STR14##

Preferred definitions of Ar include those wherein R^(b) and R^(c) areeach --CH₂ OH, --OCH₃, --CH₃ or triethylsilyloxymethyl. R^(b)preferrably resides a position 6 or 7 of the fluorenone and R^(c) ispreferrably at position 4 of the biphenyl.

The method of preparation is shown in Scheme 2 and further detailed inthe Examples. In overview, the bromide, Ar--Br undergoes metallationwith n-butyl lithium; is then boronated with B(O-i-propyl)_(3;) and isthen acidified to form Ar--B(OH)₂. Further reaction with R₄ OH and R₅ OH(R₄ and R₅ defined on page 11) provides the intermediate boronic esters.

As Exemplified hereinunder, the group Ar may optionally contain acarbonyl or other group that required protection prior to furtherprocessing.

The following examples illustrate the preparation of representativecompounds of the invention and as such are not considered as limitingthe invention as set forth in the claims. For further methods ofpreparing substituted fluorenonyl and biphenyl compounds please see U.S.Pat. Nos. 5,034,384 and 5,011,832 which are hereby incorporated byreference. Please also note that in the following Examples the compoundof Formula 2 is identified as ADC-13.

EXAMPLE 1 ##STR15## Preparation of p-Nitrobenzyl(5R,6S)-2[7-hydroxymethyl-9-fluorenone-3yl]-6-(1R-triethylsilyloxymethyl)-carba-pen-2-em-3-cazboxylatedimethylformamide mono-solvate

Anhydrous dichloromethane (7.6 L, 11.5 mL/g of ADC-13 KF≦50 mg/mL) wascharged to a dry flask under an N₂ atmosphere. ADC-13 (660 g, 1.88 mol)was added as a solid and the solution was cooled to -78° C. (thickslurry). Triethylamine (249.5 mL, 181 g, 1.79 mol) was added overapproximately 30 minutes. After 15-25 minutes, trifluoromethanesulfonicanhydride (302.4 mL, 505 g, 1.79 mol) was added over 75 minutes.Triethylamine (275.7 mL, 200 g, 1.98 mol) was added over approximately25-30 minutes, maintaining the internal temperature below -70° C. After15-25 minutes, triethylsilyl trifluoromethanesulfonate (447.3 mL, 523 g,1.98 mol) was added over 70-75 minutes, maintaining the internaltemperature below -70° C. The mixture was aged at -70° to 80° C. for45-65 minutes.

A separate dry flask was charged with anhydrous dimethylformamide (3.6L, 9.0 mL/g boronic acid) and the hydroxymethylfluorenylboronic acid(400 g, 1.57 mol) at ambient temperature under N₂ atmosphere. Thissolution was added to the TES enol triflate solution (internaltemperature maintained ≦-60° C.) over 35 minutes. To the resultingmixture was added bis(dibenzylideneacetone)palladium (0) (54.4 g, 94.2mmol, 0.06 mol/mol boronic acid) as a solid and 5.67N aqueous KOH (830.7mL, 4.71 mol, 3.0 mol/mol boronic acid). The mixture was allowed to warmto ambient temperature and stir for four hours. Ethyl acetate (3 L) wasadded and the dichloromethane was removed by vacuum concentration to avolume of 6.3 L. The resulting dark mixture was diluted with EtOAc (15L), and H₂ O (10 L). The dark layers were separated and the aqueouslayer was back extracted with EtOAc (10 L). The combined organic layerswere quantitatively assayed by HPLC and then dried by azeotropicdistillation of water and concentrated to 4.0 L.

The ethyl acetate solution was turned over to acetonitrile bydistillation. The blackish-red mixture was concentrated to a finalvolume of 17.3 L. Water (3.48 L; 20 v/v % of the acetonitrile mixture)was added. The resulting mixture was agitated for 30 minutes. Black freeflowing solids formed. The solids were removed by filtration and washed(1.44 L of 17% water in acetonitrile). The clear reddish yellow filtrate(HPLC assay showed 720 g product) was then loaded on to an SP-206 resincolumn (18 L of resin) at a flow rate of 2 b.v/h (0.5 b.v fractions[9L]). The column was eluted with: 3 b.v. (54 L) of 70/30acetonitrile/water, 2 b.v. (36 L) of acetonitrile, and 7 b.v. (126 L) of50/50 2-butanone/acetonitrile.

The appropriate fractions (assayed to contain 720 g product) werecombined and turned over to dimethylformamide (DMF) by distillation(final volume=32 L, 45 mL/g assayed product). Water (8.6 L, 12 mL/gassayed product) was added over 5 minutes. The temperature rose from 30°to 36° C. The solution was cooled to 30° C. and was seeded (5% byweight). Crystallization occurred and a yellow slurry formed as themixture was aged at 30° C. for 0.5 hours. More water (8.6 L) was addedover 4 hours (final DMF:water=15:8). The slurry was cooled to 0.5° C.over 45 minutes and aged for 1 hour. The crystals were collected byfiltration and washed with cold DMF:water (15:8; 5° C.; 7.2 L,) andwater (ambient temperature; 2×7.2 L). The wet cake was dried in vacuo(N₂ sweep, over P₂ O₅) to give 720 g (63% yield) of the coupled productas its DMF solvate (98 area % purity).

EXAMPLE 2

Preparation of p-Nitrobenzyl(5R,6S)-2-phenyl-6-(1R-triethylsilyloxy-methyl)-carba-pen-2-em-3-carboxylate##STR16##

A solution of p-nitrobenzyl7-[(1R)-1-triethylsilyloxyethyl]-2-trifluoromethane-sulfonyloxy-3-carbapenem-4-carboxylate(1 mmol), prepared as in Example 1, was diluted with toluene (4.7 mL) at-78° C. To the solution was added phenylboric acid (159 mg, 1.3 mmol.),potassium carbonate (359 mg, 2.6 mmol), TWEEN 40 (2 drops), and Pd₂(dba)₃ CHC₁₃ (20.3 mg) and the mixture was stirred for 4 hours atambient temperature. The mixture was diluted with ethyl acetate, washedwith saturated aqueous ammonium chloride and saturated aqueous sodiumchloride, dried over magnesium sulfate, and purified by silica gelchromatography using ethyl acetate and n-hexane=1.5:8.5 to give 319 mgof p-nitrobenzyl2-phenyl-7-{(1R)-1-triethyl-silyloxyethyl]-3-carbapem-4-carboxylate(61.0%) as a crystalline solid.

¹ HNMR (250 MHz CDCl₃) δ0.63 (6H, m), 0.97 (9H, t, J=7.8 Hz), 1.32(3H,d, J=6.2 Hz), 3.14-3.31 (3H, m), 4.22-4.35 (2H, m), 5.20 and 5.36(2H, ABq, J=13.9 Hz), 7.35 (5H, s), 7.44 and 8.16 (4H, ABq, J=8.6 Hz).¹³ C NMR (62.5 MHz, CDCl₃) δ4.94, 6.80, 22.72, 42.65, 52.50, 65.31,66.17, 67.34, 123.61, 126.65, 127.99, 128.06, 128.18, 129.04, 133.27,142.69, 145.85, 147.54, 160.56, and 176.51. IR (neat) 2960, 2880, 1765,1720, 1605, 1515, 1345, 1270, and 1190 cm⁻¹.

EXAMPLE 3

Preparation of p-Nitrobenzyl(5R,6S)-2-[7-methoxymethyl-9-fluorenone-3-yl]-6-(1R-triethylsilyloxy-methyl)-carbepen-2-em-3-carboxylate.##STR17##

To a solution of ADC-13 (348 mg, 1 mmol) in anhydrous tetrahydrofuran(THF) (4 mL) was added diisopropylamine (0.154 mL, 1.1 mmol) at -70° C.After 15 minutes stirring at -70° C., tifluoromethanesulfonic anhydride(0.185 mL, 1.1 mmol) was added at 72° C. to -64° C., and the mixture wasstirred at -78° C. for 20 minutes. To this mixture was addedtriethylamine (0.153 mL, 1.1 mmol) followed by triethylsilyltrifluoromethanesulfonate (0.249 mL, 1.1 mmol) at -78° C. and themixture stirred for 30 minutes at -78° C. To the reaction mixture wasadded 2-methoxymethylfluorene-9-one-6-boric acid (201 mg, 0.75 mmol),potassium carbonate (207 mg, 1.5 mmol). Pd₂ (dba)₃ CHC₁₃ (20 mg, 0.0196mmol), and TWEEN 40 (3 drops) at -78° C. and the mixture was allowed towarm to ambient temperature. After stirring for 1.5 hours, additionalpotassium carbonate (20 mg) and Pd₂ (dba)₃ CHC₁₃ (5 mg) was added. Themixture was stirred for additional 4 hours at ambient temperature. Thereaction mixture was diluted with ethyl acetate (20 mL) and washed withwater (20 mL). The aqueous layer was separated and extracted with ethylacetate (10 mL). The extract and washings were combined, dried overmagnesium sulfate, and purified by silica gel chromatography using ethylacetate and n-hexane (1:4) (v/v) to give p-nitrobenzyl2-(2-methoxymethylfluorene-9-one-6-yl)-7-{(1R)-1-triethylsilyloxyethyl]-3-carbapem-4-carboxylate(219 mg, 43.7%) as an amorphous solid.

¹ H NMR (CDCl₃, 250 MHz) δ7.96 (d, J=8.7 Hz, 2H), 7.52-7.23 (overlappingm, 7H), 7.13 (dd, J=7.6, 1.0 Hz, 1H), 5.26 (d, J=13.6 Hz, 1H), 5.09 (d,J=13.6 Hz,1H), 4.36 (s, 2H), 4.40-4.15 (m, 2H), 3.32 (s, 3H), 3.40-3.22(m, 3H), 1.22 (d, J=6.1 Hz, 3H), 0.88 (t, J=7.9 Hz, 9H), 0.58-0.49 (m,6H)

¹³ C NMR (CDCl₃) δ192.54, 176.11, 160.13, 147.33 143.96, 143.84, 142.84,142.13, 140.08, 139.74, 134.28, 134.05, 133.60, 128.28, 128.18, 127.99,123.77,123.38, 120.14, 119.96, 73.72, 67.34, 65.70, 65.44, 58.27, 52.2742.22, 22.47, 6.65, 4.75.

IR (Nujol) 1770, 1710, 1515, 1345, 1265, 1190, 1100 cm⁻¹.

EXAMPLE 4

Preparation of p-Nitrobenzyl(5R,6S)-2-[7-methyl-9-fluorenon-3-yl]-6-(1R-triethylsilyloxymethyl)-carbapen-2-em-3-carboxylate.##STR18##

Anhydrous THF (10 mL) was charged to a dry flask under N₂. ADC-13 (496mg, 1.43 mmol) was added and the solution was cooled to -78° C.Di-iso-propylamine (221 μL, 159 mg, 1.58 mmol ) was added slowly, givingan orange solution. After 15 minutes, trifluoromethanesulfonic anhydride(266 μL, 446 mg, 1.58 mmol) was added dropwise (T≦-73° C.), giving theintermediate ADC-13 enol triflate. After 1 hour, triethylamine (219 μL,159 mg, 1.58 mmol) was added dropwise, followed by triethylsilyltrifluoromethanesulfonate (357 μL, 417 mg, 1.58 mmol) (T≦-71° C.). Thepale yellow mixture was aged for 1 hour. More triethylamine (100 μL) andtriethylsilyl trifluoromethanesulfonate (160 μL) were added to consumeany remaining ADC-13 enol triflate. After 15 minutes, a solution ofTWEEN 40 (14 mg) in toluene (10 mL) was added, followed by a suspensionof the methylfluorenylboronic acid (323 mg, 1.36 mmol) in 1M aqueous K₂CO₃ (11.4 mL, 11.4 mmol). This mixture was warmed to ambienttemperature, degassed with a stream of N₂ , andtris(dibenzylidene-acetone)dipalladium chloroform complex (30 mg, 0.0286mmol) was added. This mixture was stirred at ambient temperature for 29hours. This mixture was diluted with i-PrOAc (30 mL) and was washed withH₂ O (1×25 mL) and 1N aqueous Na₂ CO₃ (1×25 mL). The combined aqueouswashings were extracted with i-PrOAc (1×10 mL). The combined organicextracts were washed with saturated aqueous NH₄ Cl (1×25 mL) and brine(1×25 mL). The organic layer was dried over anhydous MgSO₄, filtered,and purified by flash chromatography over silica gel (20% EtOAc inhexanes, then 30% EtOAc in hexanes as eluant) to give 360 mg (50% yield)of the title compound as a glassy yellow oil (purity ca. 90% by ¹ H NMRanalysis):

¹ H NMR (250 MHz, CDCl₃) δ8.18 (m, 2H), 7.60 (m, 1H), 7.48 (m, 3H), 7.38(m, 1H), 7.25 (m 3H), 5.28 (ABq, J_(AB) =13.5 Hz, Δτ_(AB) =41.4 Hz, 2H),4.31 (m, 2H), 3.30 (m, 3H), 2.39 (s, 3H) 1.32 (d, J=6.2 Hz, 3H), 0.98(t, J=8.1 Hz, 9H) 0.64 (m, 6H).

EXAMPLE 5

Preparation of p-Nitrobenzyl (5R, 6S)-2[7-triethylsilyoxymethyl-9-fluorenon-3-yl]-6-(1R-triethylsilyloxy-methyl)-carbapen-2-em-3-carboxylate##STR19##

A solution of ADC-13 (0.273 g,0.78 mmol) in the TEF (3 mL) was treatedwith di-iso-propylamine (0.122 mL, 1.1 eq) at -78° C. After 15 minutes,trifluoromethanesulfonic acid anhydride (0.145 mL, 1.1 eq) was added andthe mixture stirred at -78° C. for 20 min. Triethylamine (0.122 mL, 1.1eq) was added followed by triethylsilyl trifluoromethanesulfonate (0.196mL, 1.1 eq). The mixture was stirred at -78° C. for 1 hour. To thismixture was added triethylsilyloxymethylfluorenylboronic acid (0.1 g,0.35 eq) in a solution of toluene: tetrahydrofuran (4:1). Catalyst (Pd₂(dba)₃ CHCl₃ (0.021g)) and aqueous KOH (5.4N, 0.55 mL, 3.0 eq) wereadded and the mixture stirred at ambient temperature for 16 hours. Themixture was diluted with ethyl acetate (30 mL) and washed with water (30mL). The organic phase was dried over anhydrous MgSO₄ and purified bysilica gel chromatography (ethyl acetate:hexane) to give 190 mg (91%yield of the title compound as an amorphous solid.

¹ H NMR (250 mHz, CDCl₃) d 0.53 (m, 12H), 1.0 (m, 18H), 1.25 (d, 3H),3.3 (m, 3H), 4.2-4.4 (m, 2H), 4.7 (s, 2H) 5.15 and 5.4 (2H) 7.1-7.7 (m,8H), 8.1 (d, 2H).

EXAMPLE 6

Preparation of p-Nitrobenzyl(5R,6S)-2-[3-cyano-5-(4-hydroxymethylphenyl)-phenyl]-6-[(1R)-triethylsilyloxyeth-1-yl]carbapen-2-em-3-carboxylate.##STR20##

Dry dichloromethane (330 mL, 11.5 mL/g ADC-13, KF≦100 mg/mL) was chargedto a dry flask under a dry N₂ atmosphere. ADC-13 (28.9 g, 83.0 mmol) wasadded as a solid and the solution was cooled to -78° C. Triethylamine(11.0 mL, 7.9 g, 78.8 mmol, KF≦100 mg/mL) was added over approximately 5min, maintaining the internal temperature below -70° C. After 15 min,trifluoromethanesulfonic anhydride (13.3 mL, 22.2 g, 78.8 mmol) wasadded over approximately 15 min (exothermic!), maintaining the internaltemperature below -70° C. After 15 min, triethylamine (12.1 mL, 8.8 g,87.2 mmol, KF≦100 mg/mL) was added over approximately 5 min, maintainingthe internal temperature below -70° C. After 15 min, triethylsilyltrifluoromethanesulfonate (19.7 mL, 23.0 g, 87.2 mmol) was added overapproximately 15 min (exothermic!), maintaining the internal temperaturebelow -70° C. The mixture was aged at -70° to -80° C. for 30 min.

In a separate flask, the BBA.2H₂ O (20.0 g, 69.2 mmol) was dissolved inTHF (630 mL) and the solution was added to the enol triflate solution bycannula, maintaining the internal temperature below -60° C.Bis(dibenzylideneacetone)palladium(0) (1.2 g, 2.08 mmol) was added,followed by 5.6N aq KOH (37 mL, 208 mmol), maintaining the internaltemperature below -60° C. The cold bath was removed and the dark mixturewas allowed to warm to ambient temperature.

The reaction was quenched by pouring the mixture into 0.2M aq KH₂ PO₄(not pH adjusted, 1.1 L), EtOAc (1.3 L), and MeOH (220 mL). The mixturewas agitated and the phases (both slightly cloudy) were separated. Theaqueous layer was extracted with EtOAc (1×650 mL). The combined organicextracts were concentrated in vacuo and the residue (dark oil) wasflushed with acetonitrile (2×165 mL). The blackish-red residue wasdiluted to a final volume of 720 mL (the mixture was very turbid anddark brown in color; insoluble palladium compounds are present).

Water (145 mL; 20 v/v % of the acetonitrile mixture) was added over 1min. The resulting mixture was agitated for 30 min. Black free-flowingsolids formed. The solids were removed by filtration and washed (60 mLof 17% water in acetonitrile). The clear reddish yellow filtrate (900mL; approximate solvent composition is 16% water in acetonitrile; 1bed-volume; an HPLC assay was run to determine concentration of thecolumn feed) was then loaded onto an SP-206 resin column (900 mL ofresin).

Column Preparation:

SP-206 resin (Mitsubishi; 900 mL resin; 45 mL resin/g of biphenylboronicacid) was swelled in 50% aqueous methanol. The resin was loaded onto acolumn. The resin was washed with 2 b.v. (1800 mL) of acetone, 2 b.v.(1800 mL) of acetonitrile (ACN), and 2 b.v. (1800 mL) 70/30 ACN/water.

Chromatography:

The column feed (1 b.v., 900 mL, assayed to contain ca. 39 g of product,ca. 85% yield from BBA.2H₂ O) was loaded onto the resin (ambienttemperature) at a flow rate of 3-5 b.v./h (0.5 b.v. fractions [450 mL]).The column was eluted with: 3 b.v. (2700 mL) 70/30 acetonitrile/water,followed by 3.5 b.v. (3150 mL) acetonitrile.

The appropriate fractions (minimum collected fraction purity was 91 area%; combined fraction purity was 95 area %; assayed to contain 31.2 gproduct) were combined and evaporated in vacuo to give a pale yellow,oily foam (34.55 g, 72% from BBA.2H₂ O, 95 wt % pure vs. working std, 95area % pure (270 nm)).

The following additional compounds were prepared by the analogousprocedure:

1. Preparation ofp-Nitrobenzyl-(5R,6S)-2-(4'-t-butyldiphenylsiloxymethylphenyl)-6-[(1R-triethylsilyloxyeth-1-yl)]-carbapen-2-em-3-carboxylate##STR21## ¹ H NMR (CDCl₃, 250 MHz) δ8.18 (overlapping m, 2H), 7.75 (m,4H), 7.35-7.58 (m, 12H), 5.43 (d, J=14.0 Hz, 1H), 5.25 (d, J=14.0, 1H),4.84 (s, 2H), 4.27-4.47 (overlapping m, 2H), 3.40 (dd, J=18.1, 8.9 Hz,1H), 3.32 (overlapping m, 1H), 3.26 (dd, J=18.1, 10.0 Hz, 1H), 1.38 (d,J=6.3 Hz, 3H), 1.17 (s, tBu, 9H), 1.03 (t, J=7.6 Hz, Me, 9H), 0.07 (m,6H).

¹³ C NMR (CDCl₃) δ176.29, 160.46, 147.29, 145.72, 142.62, 142.06,135.31, 133.02, 131.47, 129.59, 127.88, 127.58, 126.08, 125.29, 123.48,123.33, 67.02 and 65.82, 65.05 and 64.91, 52.08, 42.27, 26.63, 22.47,19.10, 6.62, 4.75. IR (neat) 2973, 2895, 1769, 1720, 1608, 1522, 1347,702 cm⁻¹.

2. Preparation of p-Nitrobenzyl-(5R,6S)-2-(3'-nitrophenyl)-6-[(1R-triethylsilyloxyeth-1-yl)]-carbapen-2-em-3-carboxylate##STR22##

¹ H NMR (CDCl₃, 250 MHz) δ8.24 (t, J=1.9 Hz, 1H ), 8.12-8.23(overlapping m, 3H), 7.72 (m, 1H), 7.56 (m, 2H), 7.52 (t, J=8.5 Hz, 1H),5.38 (d, J=14.0 Hz, 1H), 5.22 (d, J=14.0 Hz, 1H), 4.38 (ddd, J=10.2,8.8, 3.0 Hz, 1H), 4.23-4.34 (m, 1H), 3.40 (dd, J=18.6, 8.8 Hz, 1H), 3.32(dd, J=5.6, 3.0 Hz, 1H), 3.24 (dd, J=18.6, 10.2 Hz, 1H), 1.32 (d, J=6.0Hz, 3H), 0.96 (t, J=7.8 Hz, 9H), 0.62 (m, 6H).

¹³ C NMR (CDCl₃) δ176.14, 160.18, 147.91, 147.68, 142.38, 142.32,134.77, 134.14, 129.13, 128.45, 128.29, 123.70, 123.59, 123.18, 67.63,65.77, 65.70, 52.22, 42.22, 22.64, 6.79, 4.92. IR (neat) 2980, 2895,1790, 1727, 1525, 1350, 1275, 1200, 750 cm⁻¹.

3. Preparation ofp-Nitrobenzyl-(5R,6S)-2-(2'-thiopheno)-6-[(1R-triethylsilyloxyeth-1-yl)]-carbapen-2-em-3-carboxylate##STR23##

¹ H NMR (CDCl₃, 250 MHz) δ8.20 (dd, J=8.7, 2.2 Hz, 2H), 7.67 (d, J=8.6Hz, 2H), 7.58 (dd, J=3.8, 1.0 Hz, 1H), 7.48 (dd, J=5.1, 1.0 Hz, 1H),7.06 (dd, J=5.1, 3.8 Hz, 1H), 5.50 (d, J=14.0 Hz, 1H), 5.28 (d, J=14.0Hz, 1H), 4.28-4.18 (m, 2H), 3.45 (dd, J=17.6, 9.8 Hz, 1H), 3.35 (dd,J=17.6, 9.3 Hz, 1H), 3.18 (dd, J=-5.9, 2.8 Hz, 1H), 1.29 (d, J=7.8 Hz,3H), 0.94 (t, J=7.8 Hz, 9H), 0.64-0.55 (m, 6H).

¹³ C NMR (CDCl₃) δ176.13, 161.09, 147.58, 143.01, 138.56, 134.32,131.62, 130.33, 128.12, 127.16, 123.68, 123.49, 67.09, 65.89, 65.38,51.47, 42.04, 22.70, 6.78, 4.91. IR (Nujol) 1770, 1705, 1600, 1565,1515, 1340, 1325, 1280, 1255, 1195 cm⁻¹.

4. Preparation of ##STR24##

¹ H NMR (CDCl₃, 250 MHz) δ8.12 (m, 1H), 7.99 (m, 2H), 7.34-7.27 (m, 9H),7.18 (m, 1H), 7.13-7.04 (m, 8H), 5.01 (d, J=13.8 Hz, 1H), 4.86 (d,J=13.8 Hz, 1H), 4.14 (q, J=5.9 Hz, 1H), 3.78 (broad, 1H), 2.99 (broad,2H), 2.89 (dd, J=18.4, 9.9 Hz, 1H), 1.16 (d, J=6.2 Hz, 3H), 0.91 (t,J=7.9 Hz, 9H), 0.60-0.50 (m, 6H).

5. Preparation ofp-Nitrobenzyl-(5R,6S)-2-(3'-cyanophenyl)-6-[(1R-triethylsilyloxyeth-1-yl)]-carbapen-2-em-3-carboxylate##STR25##

¹ H NMR (CDCl₃, 250 MHz ) δ8.16 (m, 2H), 7.65-7.40 (m, 6H), 5.36 (d,J=13.8 Hz, 1H), 5.19 (d, J=13.8 Hz, 1H) , 4.40-4.23 (m, 2H), 3.43-3.26(m, 2H), 3.18 (dd, J=18.3, 10.1 Hz, 1H), 1.29 (d, J=6.1 Hz, 3H), 0.95(t, J=7.8 Hz, 9H), 0.65-0.56 (m, 6H).

¹³ C NMR (CDCl₃, 62.9 Hz) δ176.20 160.18, 147.64, 142.61, 142.41,134,53, 132.43, 132.15, 131.70, 129.02, 128.25, 128.16, 123.68, 118.27,112.45, 67.54, 65.76, 65.61, 52.20, 42.19 , 22.61, 6.79, 4.91.

6. Preparation ofp-Nitrobenzyl-(5R,6S)-2-(4'-trifluoromethylphenyl)-6-[(1R-triethylsilyloxyeth-1-yl)]-carbapen-2-em-3-carboxylate##STR26##

¹ H NMR (CDCl₃, 250 MHz) δ8.13 (m, 2H), 7.60-7.43 (m, 6H), 5.35 (d,J=13.8 Hz, 1H), 5.18 (d, J=13.8 Hz, 1H), 4.42-4.22 (m, 2H), 3.43-3.27(m, 2H), 3.20 (dd, J=18.4, 10.1 Hz, 1H), 1.30 (d, J=6.1 Hz, 3H), 0.96(t, J=7.8 Hz, 9H)), 0.68-0.55 (m, 6H).

7. preparation of p-Nitrobenzyl-(5R,6S)-2-styryl-6-[(1R-triethylsilyloxyeth-1-yl)]-carbapen-2-em-3-carboxylate##STR27##

¹ H NMR (CDCl₃, 400 MHz) δ8.24 (m, 2H), 7.92 (d, J=16.3 Hz, 1H), 7.71(m, 2H), 7.48 (m, 2H), 7.37-7.27 (m, 3H), 6.72 (d, J=16.3 Hz, 1H), 5.51(d, J=13.9 Hz, 1H), 5.31 (d, J=13.9 Hz, 1H), 4.32-4.21 (m, 2H), 3.25(dd, J=17.6, 10.4 Hz, 1H), 3.20 (dd, J=6.2, 3.0 Hz, 1H), 3.13 (dd,J=17.6, 8.7 Hz, 1H), 1.32 (d, J=6.1 Hz, 3H), 0.98 (t, J=7.9 Hz, 9H),0.67-0.61 (m, 6H).

¹³ C NMR (CDCl₃, 100 Mz) δ175.93, 160.94, 147.62, 144.85, 143.07,136.78, 136.27, 129.00, 128.80, 128.09, 127.23, 126.73, 123.74, 121.34,67.12, 66.09, 65.23, 52.60, 36.75, 22.68, 6.80, 4.95.

IR (Nujol) 1755, 1710, 1610, 1575, 1565, 1520, 1345, 290, 1280, 1270,1230, 1200, 1155, 1110, 1070, 1015 cm-⁻¹.

8. Preparation ofp-Nitrobenzyl-(5R,6S)-2-(2'-methoxyphenyl)-6-[(1R-triethylsilyloxyeth-1-yl)]carbapen-2-em-3-carboxylate##STR28##

¹ H NMR (CDCl₃, 250 MHz ) δ8.08 (m, 2H), 7.34-b 7.23 (m, 3H), 7.13 (dd,J=7.5, 1.7 Hz, 1H), 6.94-6.83 (m, 2H), 5.27 (d, J=14.1 Hz, 1H), 5.12 (d,J=14.1 Hz, 1H), 4.35-4.19 (m, 2H), 3.73 (s, 3H), 3.31 (dd, J=18.3, 8.8Hz, 1H), 3.24 (dd, J=6.5, 2.9 Hz, 1H), 3.09 (dd, J=18.3, 10.0 Hz, 1H),1.30 (d, J=6.2 Hz, 3H), 0.95 (t, J=7.9 Hz, 9H), 0.68-0.52 (m, 6H).

¹³ C NMR (CDCl₃, 62.9 MHz) δ176.70, 160.49, 156.26, 147.41, 143.42,142.88, 129.98, 129.46, 128.16, 127.81, 123.51, 122.95, 120.34, 110.83,67.24, 66.34, 65.04., 55.37, 53.19, 41.80, 22.72, 6.81, 4.95.

IR 2970, 2890, 1770, 1720, 1610, 1600, 1520, 1480, 1460, 1440, 1380,1350, 1270, 1195 cm⁻¹

EXAMPLE 7

Preparation of p-Nitrobenzyl(1S,5R,6S)-1-methyl-2-(7-hydroxymethyl-9-fluorenone-3-yl)-6-(1R-triethylsilyloxyethyl)-carbapen-2-em-3-carboxylate.##STR29## p-Nitrobenzyl(1R,5R,6S)-1-methyl-2-oxo-6-(1R-hydroxyethyl)-carbapenam-3-carboxylate

(3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl]-azetidin-2-one(390 mg, 1 mmol) was dissolved in anhydrous methylene chloride (8 ml)and treated with Rhodium octanoate (3 mg). The reaction mixture wasrefluxed under nitrogen for 4 hours then allowed to cool and evaporatedunder reduced pressure to give the desired cyclized product which wasused for the next reaction without further purification.

p-Nitrobenzyl(1S,5R,6S)-1-methyl-2-(7-hydroxymethyl-9-fluorenone-3-yl)-6-(1R-triethylsilyloxyethyl)-carbapen-2-em-3-carboxylate

The product from the previous reaction was dissolved in methylenechloride (4 ml) and cooled to -78°, under nitrogen. Triethylamine (133μl, 0.95 eq.) was added dropwise and the reaction mixture was stirredfor 15 minutes followed by dropwise addition of trifluoromethanesulfonicanhydride (159 μl, 0.95 eq.). The reaction mixture was stirred at -78°for 25 min. To this was added triethylamine (153 μl, 1.1 eq) dropwisefollowed 15 minutes later, by triethylsilyl trifluoromethanesulfonate(193 μl, 1.1 eq) also added dropwise. The reaction mixture was stirredanother 1.25 hours at the end of which TLC showed complete reaction tothe triethylsilyl derivative. The hydroxymethylflourenone-boronic acid(254 mg, 1.0 eq) was dissolved in DMF (2.2 ml) and added dropwise to thereaction mixture followed by pd₂ (dibenzylideneacetone)3CHCl₃ (21 mg)and KOH solution (0.52 ml, 5.67N). The reaction mixture was stirred at-78° for 10 minutes and then allowed to warm to room temperature in 15minutes and then stirred at 30° for 3.5 hours. TLC showed completereact,ion of the enoltriflate.

The reaction mixture was diluted with 20% EtOAc/Et₂ O (50 ml) and washedfour times with water (25 ml) and then with brine. The organic phase wasdried over Na₂ SO₄ and evaporated to give a residue (502 mg).Chromatography on silica gel plates (35% EtOAc/hexane eluant) gave theproduct (331 mg).

NMR (200 MHz, CDCl₃): δ0.62 (q, J=7, CH₃ --CH₂ --Si); 0.97 (t, J=7, CH₃--CH₂ --Si); 1.12 (d, J=7.5, 1-β-CH₃); 1.33 (d, J=7.5, CH₃ --CHOH); 3.38(d,d J=3, J=7, C-6H); 3.45 (m, C-1H); 4.31 (m, CH₃ CHOH); 4.2 (d,d J=3,J=10.5 C-5H); 4.7 (s, CH₂ OH); 5.18 (ABq, ARCH₂ O); 7.12-8.05 (m, ArH).

EXAMPLE 8

1. Preparation of 2-Methoxymethylfluoren-9-on-6ylboronic Acid bysolvolysis/ketalization protection steps followed bymetallation/borylation.

A. Solvolysis and Ketalization Reactions

Preparation of 6-Bromo-2-methoxymethyl-9-fluorenone Dimethyl Ketal##STR30## Part a-(conversion of benzylic bromide to methyl ether):

Absolute methyl alcohol (200 mL; 10 mL/g) was charged to a dryglass-lined pressure-rated (to 100 psi) vessel equipped with amechanical stirrer under a N₂ atmosphere.6-Bromo-2-bromomethyl-9fluorenon (20 g; 0.057 mol) was charged and theresulting slurry was heated at 100° C. in the sealed vessel for 24hours. The mixture was cooled to room temperature. The methyl ethercrystallized upon cooling.

(Ketalization of the carbonyl):

The reaction mixture from Part 4a was cooled to 0-5° C. and sequentiallycharged with concentrated sulfuric acid (4.6 mL; added dropwise toprevent splattering, exothermic) and trimethyl orthoformate (93.5 mL,0.855 mol; slightly endothermic). The reaction flask was fitted with adistillation head and the reaction mixture was heated and distillate wascollected (˜60 mL) until the internal temperature reached 60° C. (stillhead temperature: 55° C.). The reaction mixture was then heated at 60°C. under reflux for 1.5 hours. The colorless to pale yellow solution wascooled to 10° C. Triethylamine (47.7 mL, 34.6 g, 0.34 mol; 4 mol/mol ofH₂ SO₄ ; KF≦100 μg/mL) was added to the stirred mixture. The solutionwas taken to a minimum volume (˜57 mL) by distillation in vacuo(internal temperature≦30° C.). The mixture was diluted with toluene (400mL) and aqueous NaOH solution (400 mL, 1.0N) and agitated. The phases(both cloudy) were separated and the aqueous phase was extracted withtoluene (200 mL). The combined organic phases were washed twice withD.I. water (200 mL). The organic phase was filtered into the nextreaction vessel (suitable for cryogenic reactions) (clear solution atthis point) and azeotropically dried by vacuum distillation of toluene(internal temperature≦53° C.) to a KF≦100 μg/mL. The solution wasreduced to a minimum volume (57 mL) prior to the next reaction.

B. Metallation/Boronation

Preparation of 2-Methoxymethylfluoren-9-on-6-ylboronic Acid ##STR31##

Into a dry three liter three necked round bottom flask equipped with a500 mL addition funnel, thermocouple probe, and nitrogen inlet, werecharged the solution of ketal in toluene (420 mL, 1.07M) andtetrahydrofuran (1.7 L, KF<44 μg/mL) at room temperature. The air in thereaction flask was exchanged by three vacuum purges with nitrogen. Asample is taken to verify a KF<100 μg/mL. Triisopropyl borate (150 mL,651 mmol) was added to the solution at room temperature. The mixture wascooled to -78° C. and n-butyl lithium solution (1.6M in hexanes; 395 mL;628 mmol) was slowly added over 3 hours, maintaining the temperature at-80° to -75° C. After 30 minutes, an aliquot of the reaction mixture wastaken and quenched into acetic acid for HPLC assay. Typically, 2.0 area% of the bromo compound remained. Additional n-butyl lithium solution(1.6M; 19 mL; 30.4 mmol) was added to the reaction mixture over 10minutes at -80° to -75° C. After aging for 20 minutes, a reactionaliquot was assayed by HPLC. In a typical case, 0.1 area % of the bromocompound remained. The reaction mixture was allowed to warmed to 20° C.over 1 hour. To the solution was added aqueous sulfuric acid (2M; 920mL; 1.84 mol) over 10 minutes. The reaction temperature rose to 28° C.The mixture was vigorously stirred for 30 minutes. The organic layer(2.62 L) was separated. The aqueous layer (1.2 L) was extracted withethyl acetate (0.5 L and 0.2 L). The combined organic extracts wereconcentrated to 300 mL under 165 mm bar (38° C. bath). The productcrystallized out. To this mixture was added DI water (450 mL), and theresulting three phase mixture was stirred overnight at room temperature.The precipitates were collected on a 600 mL sintered glass filtered,washed with toluene (100 mL) and DI water (3×150 mL), and dried underhouse vacuum (nitrogen sweep) at 80° C. overnight (filter cake; 9.8 cmID×2.5 cm). 2-Methoxymethylfluoren-9-one-6-boric acid was obtained as amono-hydrate (125.8 g, 91.1 wt % purity) in 95.2% corrected yield.

2. Preparation of 5-cyano-4 '-hydroxyoxymethylbiphenyl-3-boronic acid##STR32##

To 1-bromo-4-tert-butyldiphenylsilyloxymethylbenzene (1.224 Kg; 2.32mol) was added dry (KF<50 μg/mL) THF (10.5 L) and B(OiPr)₃ (794 mL; 3.44mol; 1.48 eq) at room temperature under nitrogen. The air in thereaction flask was completely exchanged by three vacuum purges withnitrogen. A sample is taken to verify a KF<100 μg/mL. The solution wascooled down to -78° C. To the solution was added 1.6M solution of n-BuLiin hexanes (2.08 L; 3.32 mol; 1.43 eq) at -78° to -75° C. over 2 hours.The mixture was allowed to warm up to 17° C. To the mixture was added 4MH₂ SO₄ (4.64 L) at 5° C. The reaction was slightly exothermic and thetemperature rose to 10° C. The reaction mixture was refluxing for 48hours.

After cooling down to room temperature, 5M aqueous potassium hydroxide(7.7 L) was dropwise added to the mixture below 20° C. (pH was about10.8). During nutralization, inorganic salt (K₂ SO₄) was precipitated.To this mixture was added 1M aqueous potassium hydroxide (2.23 L) below20° C. (pH was about 12.5). To this mixture was added t-butylmethylether (5 L) and stirred at room temperature for 30 minutes. The aqueouslayer was separated and THF (2.5 L) was added to the aqueous solution.The aqueous solution was adjusted it pH to 2.7 with conc. HCl (about 374mL) below 20° C. The mixture was extracted after stirring with ethylacetate (5 L), dried over MgSO₄ (about 200 g), and concentrated invacuo. The residual solid was dissolved in DMF (2.3 L) at 100° C. andadded DI water (6.9 L) at 100° C. The mixture was cooled down to roomtemperature gently and aged at ambient temperature overnight. Thecrystals were collected by filtration, washed with 30% cold aqueous DMF(2 L) and then DI water (2 L), and dried in over at room temperatureovernight to give 524 g of the desired boronic acid.

What is claimed is:
 1. A process of making a 2-aryl carbapenem compoundof Formula I, ##STR33## wherein Ar is ##STR34## wherein: R^(a) is(a) CN,(b) CF₃, (c) C₁₋₃ alkoxy, (d) --NO₂, (e) hydroxy C₁₋₃ alkyl, wherein thehydroxy is optionally protected with a silyl protecting group selectedfrom tri-C₁₋₄ alkyl silyl, phenyl di C₁₋₄ alkyl and diphenyl mono C₁₋₄alkyl silyl; (f) substituted tetrazolyl wherein the substituent ishydrogen, C₁₋₃ alkyl, halo, hydroxy or C₁₋₃ alkoxy; R^(b) is(a) C₁₋₃alkyl, (b) C₁₋₃ alkoxy, (c) substituted C₁₋₃ alkyl, wherein thesubstituent is hydroxy, or (d) hydroxy C₁₋₃ alkyl, wherein the hydroxyis optionally protected with a silyl protecting group selected fromtri-C₁₋₄ alkyl silyl, phenyl di-C₁₋₄ alkyl and diphenyl mono C₁₋₄ alkylsilyl; R^(c) is(a) C₁₋₃ alkyl, (b) hydroxy C₁₋₃ alkyl, wherein thehydroxy is optionally protected with a silyl protecting group selectedfrom tri-C₁₋₄ alkyl silyl, phenyl di C₁₋₄ alkyl and diphenyl mono C₁₋₄alkyl silyl; R₁ is(a) benzyl, (b) p-methoxybenzyl, (c) p-nitrobenzyl,(d) o-nitrobenzyl, (e) benzhydryl, (f) allyl, (g) 2-trimethylsilylethylor (h) 2,2,2-trichloroethyl; R₃ is(a) hydrogen, (b) a hydroxy protectinggroup selected from tri-C₁₋₄ alkyl silyl, phenyl di C₁₋₄ alkyl anddiphenyl mono C₁₋₄ alkyl silyl; (c) --C(O)OR'₃, wherein R'₃ is(a)benzyl, (b) p-methoxybenzyl, (c) p-nitrobenzyl, (d) o-nitrobenzyl, (e)benzhydryl, (f) allyl, (g) 2-trimethylsilylethyl or (h)2,2,2-trichloroethyl; (d) CH₂ OR'₃, or (e) R'₃ ; R₇ is hydrogen ormethyl including β-methyl;comprising: contacting a compound of formula B##STR35## --OR₂ represents (a) triflate;(b) fluorosulfonate; (c)mesylate; (d) tosylate or (e) diarylphosphate wherein aryl is mono ordisubstituted phenyl and the substituents are each independentlyhydrogen or halo;and a coupling base in a coupling solvent with acompound of Formula ##STR36## and a transitional metal catalyst to yielda compound of Formula 1 wherein R₄ and R₅ are each individually hydrogenor C₁₋₆ alkyl or R₄ and R₅ taken together are C₁₋₆ alkyl or R₄ and R₅are joined together as to form ##STR37## wherein R₆ is C₁₋₃ alkyl, halo,hydroxy, C₁₋₃ alkoxy or hydrogen.
 2. A process according to claim 1wherein the transition metal catalyst is Pd (dihenzyledineacetone)₂. 3.A process according to claim 1 further comprising:contacting thecompound of formula A: ##STR38## in a non-reactive solvent with aprotecting agent R₃ X suitable for removably protecting a hydroxyl groupin the presence of a nitrogen containing base to yield a compound ofFormula B ##STR39## wherein R₃ is selected from the group consisting oftri-C₁₋₄ alkyl silyl, phenyl di C₁₋₄ alkyl and diphenyl mono C₁₋₄ alkylsilyl, and X represents a leaving group.
 4. A process according to claim3 wherein the non-reactive solvent is dichloromethane.
 5. A processaccording to claim 4 wherein the protecting agent is triethylsilyltrifluoromethane sulfonate.
 6. A process of making a 2-aryl carbapenemcompound of Formula 1, ##STR40## wherein Ar is ##STR41## wherein R^(a)is(a) CN, (b) CF₃, (c) C₁₋₃ alkoxy, (d) --NO₂, (e) hydroxy C₁₋₃ alkyl,wherein the hydroxy is optionally protected with a silyl protectinggroup selected from tri-C₁₋₄ alkyl silyl, phenyl di C₁₋₄ alkyl anddiphenyl mono C₁₋₄ alkyl silyl; (f) substituted tetrazolyl; R^(b) is(a)C₁₋₃ alkyl, (b) C₁₋₃ alkoxy, (c) substituted C₁₋₃ alkyl, wherein thesubstituent is hydroxy, or (d) hydroxy C₁₋₃ alkyl, wherein the hydroxyis optionally protected with a silyl protecting group selected fromtri-C₁₋₄ alkyl silyl, phenyl di C₁₋₄ alkyl and diphenyl mono C₁₋₄ alkylsilyl; R^(c) is(a) C₁₋₃ alkyl, (b) hydroxy C₁₋₃ alkyl, wherein thehydroxy is optionally protected with a silyl protecting group selectedfrom tri-C₁₋₄ alkyl silyl, phenyl di C₁₋₄ alkyl and diphenyl mono C₁₋₄alkyl silyl; R₁ is(a) benzyl, (b) p-methoxybenzyl, (c) p-nitrobenzyl,(d) o-nitrobenzyl, (e) benzhydryl (f) allyl, (g) 2-trimethylsilylethylor (h) 2,2,2-trichloroethyl; R₃ is(a) hydrogen, (b) a hydroxy protectinggroup selected from tri-C₁₋₄ alkyl silyl, phenyl di C₁₋₄ alkyl anddiphenyl mono C₁₋₄ alkyl silyl; (c) --C(O)OR'₃, wherein R'₃ is(a)benzyl, (b) p-methoxybenzyl, (c) p-nitrobenzyl, (d) o-nitrobenzyl, (e)benzhydryl (f) allyl, (g) 2-trimethylsilylethyl or (h)2,2,2-trichloroethyl; (d) CH₂ OR'₃, or (e) R'₃ ; R₇ is hydrogen ormethyl, including β-methyl;Comprising (A) contacting a compound ofFormula 2 ##STR42## in a non-reactive solvent with an activating agentin the presence of a base to yield a compound of formula A; ##STR43##wherein --OR₂ is a good leaving group selected from(a) triflate, (b)fluorosulfonate, (c) mesylate, (d) tosylate, (e) diaryl phosphatewherein the aryl group is mono or disubstituted phenyl and thesubstituents are each independently hydrogen or halo; (B) Contacting thecompound of formula A in non-reactive solvent with a protecting agentsuitable for removably protecting the hydroxyl of Formula A in thepresence of a nitrogen containing base to yield a compound of Formula B##STR44## wherein the protecting agent is R₃ X, consisting of aprotecting group R₃ and a good leaving group X. (C) Contacting thecompound of Formula B and a coupling base in a coupling solvent with acompound of formula ##STR45## and a palladium catalyst to yield acompound of Formula 1 wherein R₄ and R₅ are each individually hydrogenor C₁₋₆ alkyl or R₄ and R₅ taken together are C₁₋₆ alkyl or R₄ and R₅are joined together as to form ##STR46## wherein R₆ is C₁₋₃ alkyl, halo,hydroxy, C₁₋₃ alkoxy or hydrogen.
 7. A process of making a 2-arylcarbapenem compound of Formula I, ##STR47## wherein: R₁ isp-nitrobenzyl;R₃ is triethylsilyl, R₇ is hydrogen, and Ar is ##STR48##comprising: contacting a compound of formula B ##STR49## wherein OR₂represents triflateand a coupling base in a coupling solvent with acompound of Formula ##STR50## and a transition metal catalyst to yield acompound of Formula 1 wherein R₄ and R₅ are each individually hydrogenor C₁₋₆ alkyl or R₄ and R₅ taken together are C₁₋₆ alkyl or R₄ and R₅are joined together as to form ##STR51## wherein R₆ is C₁₋₃ alkyl, halo,hydroxy, C₁₋₃ alkoxy or hydrogen.
 8. A process according to claim 7wherein the palladium catalyst is Pd (dibenzyledineacetone)₂.
 9. Aprocess according to claim 7 further comprising:contacting the compoundof formula A: ##STR52## in a non-reactive solvent with a protectingagent suitable for removably protecting a hydroxy group in the presenceof a nitrogen containing base to yield a compound of Formula B ##STR53##wherein the protecting agent is R₃ X, consisting of a protecting groupR₃ which is triethylsilyl and a leaving group X.
 10. A process accordingto claim 9 wherein the non-reactive solvent is dichloromethane.
 11. Aprocess according to claim 10 wherein the protecting agent istriethylsilyl trifluoromethane sulfonate.
 12. A process of making a2-aryl carbapenem compound of Formula 1, whereinR₁ is p-nitrobenzyl,--OR₂ is triflate, R₃ is triethylsilyl, R₇ is hydrogen, Ar is ##STR54##comprising (A) contacting a compound of Formula 2 ##STR55## in anon-reactive solvent with an activating agent in the presence of a baseto yield a compound of formula A; ##STR56## (B) Contacting the compoundof formula A in the non-reactive solvent, with a protecting agentsuitable for removably protecting the hydroxyl of Formula 2 in thepresence of a nitrogen containing base to yield a compound of Formula B##STR57## wherein the protecting agent is R₃ X, and X is a good leavinggroup; (C) Contacting the compound of Formula B and a coupling base in acoupling solvent with a compound of formula ##STR58## and a palladiumcatalyst to yield a compound of Formula 1, ##STR59## wherein R₄ and R₅are each individually hydrogen or C₁₋₆ alkyl or R₄ and R₅ taken togetherare C₁₋₆ alkyl or R₄ and R₅ are joined together as to form ##STR60##wherein R₆ is C₁₋₃ alkyl, halo, hydroxy, C₁₋₃ alkoxy or hydrogen.